Ketamine for Treatment-Resistant Depression

Ketamine is a relatively new option for managing treatment-resistant depression that has a different mechanism of action from other antidepressant medications. Ketamine itself isn’t new, though; it’s a dissociative anaesthetic that’s also known by its club drug name Special K.

Over the last 10-15 years, multiple research trials have shown that it has an antidepressant effect with a rapid onset (such as this study published in The American Journal of Psychiatry). It starts working within about 24 hours, which is a huge improvement over oral antidepressants that can take a few weeks to really see an effect.

Ketamine increases rates of remission in major depressive disorder and bipolar depression, but the effect is not as pronounced in the latter. It appears to have a protective effect against suicide, and unlike many antidepressants, it doesn’t appear to trigger mania.

Ketamine’s mechanism of action

Ketamine’s mechanism of action is different from other antidepressant medications. It acts on NMDA and AMPA receptors, affecting the balance between the calming neurotransmitter GABA and the excitatory/stress neurotransmitter glutamate.

It also boosts the production of BDNF (brain-derived neurotrophic factor), which in turn promotes brain health and neuroplasticity. This mechanism may be why ketamine has antidepressant effects while other drugs that act on NMDA receptors don’t.

Some research suggests that people with depression may have abnormalities related to their NMDA receptors. This can produce glutamate overactivity, leading to hyperexcitation in the brain, known as excitotoxicity.

Dosing

Ketamine is typically given at a dose of 0.4-0.5 mg per kg of body weight, which is lower than the usual anesthesia dose. It’s given in 1-2 doses per week as an intravenous infusion. The effect from each dose typically lasts 3-7 days, but it can last up to 15 days.

There’s also a nasal spray formulation that delivers esketamine. Ketamine consists of two mirror-image molecules, abbreviated as S and R. Esketamine is the S-ketamine molecule only.

Whether a patient is receiving a ketamine infusion or the esketamine nasal spray, the treatment is administered in a facility where the patient can be medically monitored for a couple of hours. Injectable ketamine is cheap, but the need for monitoring makes the ketamine package deal pretty pricey.

Side effects

Side effects are supposed to be generally mild and wear off within 2 hours. While harmful effects on the bladder can occur at high doses, this hasn’t been demonstrated at the doses used for depression treatment. Dissociative effects can occur during the infusion and in that 2-hour window after the dose, which could potentially limit the tolerability for some people.

It can trigger spikes in heart rate and blood pressure, as well as headaches, dizziness, blurred vision, drowsiness, abnormal sensations, and perceptual disturbances. Patients remain in the clinic for a period of time following the dose so that they can be monitored.

Issues with access

Ketamine hasn’t been approved by the US Food and Drug Administration (FDA) or Health Canada for the treatment of depression, so its use is considered “off-label”. Esketamine, on the other hand, has been approved in both countries to treat depression.

It seems like ketamine/esketamine treatment is fairly easy to access in the US if people have good insurance. In Canada, it’s a lot more challenging to get. With depression being an off-label use for ketamine, the public health care system isn’t exactly clamouring to use it on patients. In British Columbia, the province where I live, both ketamine and esketamine can only be administered in an “accredited non-hospital facility“, and they’re not covered by the provincial Pharmacare plan. If I wanted ketamine treatment in Vancouver, I would have to pay $6750 out of pocket for 10 treatments. That’s a hell of a lot of money.

What does the future hold?

I hope that Health Canada will approve ketamine for use in major depressive disorder; perhaps that would get the ball rolling and result in ketamine treatment being offered through the public health care system.

Ideally, researchers will come up with another drug that has the same kind of therapeutic effect as ketamine without the anaesthetic/dissociative effects. Hopefully, that will be coming down the pike sooner rather than later.

Being treatment-resistant sucks, and I need something that works in a different way from all the stuff I’ve already tried. Unfortunately, it doesn’t look like that’s going to be happening anytime soon unless the tooth fairy leaves a big cheque under my pillow.

Have you had any experience with ketamine?